Metabolomics is a systematic detection and study of the metabolites (small biomolecules <2000 Dalton) present in samples derived from living systems. Recent advances in ultra-high resolution mass spectrometry enables rapid detection of tens of thousands of isotopologues (i.e. mass equivalent sets of isotopomers) representing thousands of metabolites. Yet, the necessity for metabolite identification, quantitative analysis, and interpretation, within the context of relevant metabolic networks, represents key barriers to the use of this avalanche of information-rich, phenotypic metabolomics data. In fact, over 50% of detected metabolites remain unidentified in ultra-high resolution mass spectra and there is low confidence in those metabolites identified without a comparison to standards. With stable isotope-resolved metabolomics (SIRM) experiments, comparison to millions (or billions) of isotopically-different chemical standards is not possible.